Page 44 - Read Online

Page 2 of 7 Lo. Hepatoma Res 2019;5:41 I http://dx.doi.org/10.20517/2394-5079.2019.021

in distinguishing HCC from its precursor lesions or other liver nodules. With reference to the multi-step
process of hepatocarcinogenesis which could also be observed histologically, some classification systems
have been proposed for HCC. For instance, the terms “early HCC” and “progressed HCC” have been
[1]
defined based on the size and differentiation of tumor . In recent years, further investigations have been
carried out on the subtyping of HCC specifically referencing the morphological characteristics of tumor
cells. The significance of these subtypes was further substantiated by their clinical relevance and the genetic
makeup. In the latest 5th edition of the World Health Organization (WHO) Classification of Digestive
[2]
System Tumors, several histological subtypes were described . In this review, we will focus on elaborating
the recent understanding on 5 subtypes: macrotrabecular-massive HCC (MTM-HCC), steatohepatitic
HCC (SH-HCC), lymphocyte-rich HCC, scirrhous HCC and fibrolamellar carcinoma (FLC). In addition,
an update on the entity combined hepatocellular-cholangiocarcinoma (cHCC-CCA) will be discussed.

MTM-HCC
Published in 2018, histological review of clinical samples archive led to the identification of a novel and
distinct subtype of HCC defined by the histological features of tumor cells - MTM-HCC. It is defined as
the presence of macrotrabeculae of more than 6 cells thick in > 50% tumor, and was identified in 16% on
[3]
average in 2 large cohorts comprising 237 surgical resection samples and 284 biopsy samples . And this
subtype was statistically associated with aggressive parameters including tumor size, alpha-fetoprotein
(AFP) levels, satellite nodules and vascular invasion. Besides, it was an independent prognosticator for
[3]
early recurrence (within 2 years) and overall recurrence . The prognostic significance was further validated
[4]
[5]
by other group . In another study by Jeon et al. , MTM-HCC, as defined by > 30% of macrotrabecular
pattern, was associated with large tumor, hepatitis B virus infection, and less frequent cirrhosis. This
subtype was also found to be associated with higher tumor grade, tumor stage, higher AFP level, and a
worse recurrence-free survival.

In addition, investigations were carried out to identify specific radiological, immunohistochemical, and
genetic features of this entity. Radiologically, MTM-HCC was reported to preferentially demonstrate
[6]
irregular rim-like arterial phase enhancement on gadoxetate-enhanced magnetic resonance imaging .
[7]
Extending from their initial observation, Calderaro et al. attempted to identify potential biomarkers
for this entity. On analysis of the TCGA dataset, endothelial-specific molecule 1 (ESM1) was identified
and validated as a biomarker for MTM-HCC. In addition, angiotensin 2 and VEGFA overexpression was
[8]
observed in MTM subtype . Recent studies also shed light on the genetic composition of MTM-HCC,
which was found to be related to cell cycle activation, chromosomal instability, the G3 transcriptomic
[8]
[9]
[8]
subgroup according to Boyault et al. and TP53 mutation .
SH-HCC
[10]
The steatohepatitic subtype was first described by Salomao et al. . It is characterized by prominent
steatotic changes in the tumor cells namely fat accumulation, ballooning degeneration, presence Mallory-
Denk bodies and peri-cellular fibrosis. In a study examining HCV-related liver explants, SH-HCC was
[10]
identified in 35.5% of the cohort . According to a follow-up study by the same group in 2012, SH-HCC
[11]
constituted 14% of HCC explants . A more recent paper reported a diagnosis of SH-HCC in around 20%
[12]
of 96 HCC cases reviewed, and made an observation that SH-HCC was not associated with cirrhosis .
It was noted that around 60% (14 of 22) SH-HCCs was associated with one more known risk factor for
[10]
non-alcoholic fatty liver disease (NAFLD) . The association with and NAFLD and metabolic syndrome
was consolidated in other studies [13,14] . While most studies suggested a link of fatty liver disease with this
[15]
subtype, in 2015 Yeh et al. looked at a series of SH-HCC and identified a group of patients without any
underlying causes for metabolic disease.